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Overcoming multidrug resistance in human carcinoma cells by an antisense oligodeoxynucleotide--doxorubicin conjugate in vitro and in vivo.

Abstract：

:Multidrug resistance (MDR), a major obstacle to successful cancer chemotherapy, may be induced by amplification of the MDR1 gene and overexpression of the P-glycoprotein (P-gp), which acts as drug efflux pump decreasing intracellular drug accumulation. In this study, an antisense oligodeoxynucleotide--doxorubicin conjugate was used to overcome MDR in a human carcinoma-resistant cell line, both in vitro and in vivo, through downregulation of P-gp expression and mRNA levels. Compared with the unmodified antisense-oligodeoxynucleotide (AS-ODN), the conjugate markedly inhibited P-gp expression and mRNA levels. With in vitro treatment with the conjugate, the intracellular accumulation of doxorubicin (DOX) was increased 4.4-fold compared to treatment with DOX alone; by contrast, a 2.2-fold increase was observed when treated with AS-ODN alone. In the in vivo studies, it was approximately 3.5-fold higher compared to the control group treatment with DOX alone and 2.1-fold higher than found with AS-ODN. The weight of tumors formed was markedly decreased after conjugate treatment as compared to either treatments with AS-ODN or DOX alone. Furthermore, treatment with combinations of the agents appeared to be well tolerated. These results suggest that a strategy using the conjugate in combination with antitumor drugs may comprise a powerful treatment for MDR.

journal_name

Mol Pharm

journal_title

Molecular pharmaceutics

authors

Ren Y,Wang Y,Zhang Y,Wei D

doi

10.1021/mp800001j

subject

Has Abstract

pub_date

2008-07-01 00:00:00

pages

579-87

issue

4

eissn

1543-8384

issn

1543-8392

journal_volume

5

pub_type

杂志文章

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